Phase 1 Trial of Arginine Hydrochloride for the Management of Diabetic Ketoacidosis in Type 2 Diabetes

NCT07167693 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 24-12-7395
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Diabetic ketoacidosis (DKA) is increasingly recognized in adults with "ketone-prone" type 2 diabetes. In many of these patients, the pancreas can still make insulin but becomes temporarily "stunned" during severe, prolonged high blood sugar. Arginine is a naturally occurring amino acid that can trigger the pancreas to release its own insulin when glucose is high. It is FDA-approved for other uses and has been given intravenously for decades with a strong safety record. Whether a single arginine infusion given early during DKA can safely boost the body's insulin and speed recovery has not been tested. This randomized, double-blind, placebo-controlled, phase 1/2 trial will enroll 60 adults who present to one of four Detroit-area emergency departments with DKA consistent with ketone-prone type 2 diabetes (high glucose and significant ketones). Participants will receive standard DKA care ordered by their clinicians. In addition, under blinded conditions they will receive either arginine hydrochloride 30 grams (in 300 mL) or placebo (normal saline), infused intravenously over 30 minutes as early as feasible after DKA is recognized. The main question is whether arginine increases endogenous (self-made) insulin soon after infusion. We will measure C-peptide (a marker released in equal amounts with insulin) and glucose at 10, 30, and 90 minutes after the start of the infusion and calculate the C-peptide/glucose ratio. Secondary measures include the rate of ketone (β-hydroxybutyrate) clearance and the total insulin dose required in the first 24 hours. Additional blood tests will examine arginine and related amino acids, and a small sample of platelets will be used to explore mitochondrial function. Safety will be closely monitored during and after the infusion, and participants will be contacted at 90 days to assess for any delayed problems. Potential risks include temporary flushing, nausea, or headache; the infusion can be stopped at any time if needed. Potential benefits include faster resolution of ketosis and reduced insulin needs, but benefits cannot be guaranteed for individual participants.

Conditions

Hyperglycaemia (Diabetic); Diabetes (DM); Diabetic Ketoacidosis; Ketosis Prone Diabetes

Keywords

Arginine hydrochloride; Arginine; R-Gene 10; Insulin secretagogue; Endogenous insulin secretion; C-peptide; C-peptide to glucose ratio; Type 2 ketosis-prone diabetes (T2KPD); Flatbush diabetes; Ketosis-prone diabetes (KPD); Hyperglycemic crisis; Nitric oxide (NO); Global arginine bioavailability ratio (GABR); Mitochondrial function

Outcome Measures

Primary Outcomes (1)

• Change in endogenous insulin secretion (C-peptide/glucose ratio)

  Serum C-peptide (ng/mL) and plasma glucose (mg/dL) will be measured at 0 (pre-infusion), 10, 30, and 90 minutes from infusion start. The C-peptide/glucose ratio will be calculated at each time. Primary summary = change from baseline to 90 minutes (90-min ratio minus baseline ratio). Higher values indicate greater recruitable endogenous insulin secretion.

  Baseline (pre-infusion) to 90 minutes after infusion start

Secondary Outcomes (5)

• Change in beta-hydroxybutyrate (BHB) concentration

  Baseline to 24 hours

• Rate of BHB clearance

  0-24 hours

• Total insulin administered in first 24 hours

  0-24 hours

• Plasma arginine concentration (change from baseline)

  Baseline to 90 minutes

• Global Arginine Bioavailability Ratio (GABR)

  Baseline to 90 minutes

Other Outcomes (2)

• Platelet mitochondrial complex IV activity (change from baseline)

  Baseline to 90 minutes

• Platelet mitochondrial complex V (ATP synthase) activity (change from baseline)

  Baseline to 90 minutes

Study Arms (2)

Arginine Hydrochloride 30 g IV + Standard DKA Care

ACTIVE COMPARATOR

Single, blinded 30-minute intravenous infusion of arginine hydrochloride 30 g/300 mL (R-Gene® 10), initiated as early as feasible after recognition of DKA, in addition to standard DKA management (fluids, insulin, electrolytes) at the treating clinician's discretion. Infusion procedures are matched to placebo (covered containers; standardized pump settings) to maintain blinding. Study blood draws occur at 0 (pre-infusion), 10, 30, and 90 minutes for C-peptide/glucose and targeted amino acids; clinical labs are used to assess β-hydroxybutyrate clearance and total insulin administered in the first 24 h.

Drug: Arginine hydrochloride

Placebo (0.9% Saline) IV + Standard DKA Care

PLACEBO COMPARATOR

Single, blinded 30-minute intravenous infusion of matching placebo: 0.9% sodium chloride (normal saline) in a 500 mL container, administered at a standardized rate to mimic the active arm, plus standard DKA management directed by the treating team. Appearance and administration procedures match the arginine arm (covered containers; identical pumps/tubing) to preserve blinding. Study blood draws and assessments occur on the same schedule as the arginine arm (0, 10, 30, and 90 minutes).

Drug: Sodium Chloride 0.9%

Interventions

Arginine hydrochloride DRUG

Single intravenous infusion of arginine hydrochloride 30 g in 300 mL 10% solution (R-Gene® 10), administered over 30 minutes via infusion pump. Given as early as feasible after recognition of DKA and in addition to standard DKA care (fluids, insulin, electrolytes) at the treating clinician's discretion. Investigational pharmacy prepares and dispenses blinded study drug; containers are covered to mask appearance and infusion parameters match placebo. Continuous safety monitoring with prespecified stop criteria. Study blood draws at 0 (pre-infusion), 10, 30, and 90 minutes for C-peptide/glucose and amino acids; clinical labs track β-hydroxybutyrate clearance and total insulin over 24 hours.

Also known as: L-arginine hydrochloride, Arginine HCl, R-Gene 10, Arginine hydrochloride injection 10%

Arginine Hydrochloride 30 g IV + Standard DKA Care

Sodium Chloride 0.9% DRUG

Placebo comparator: 0.9% sodium chloride administered as a single 30-minute intravenous infusion using identical tubing, pump settings, and covered container as the active arm to preserve blinding. Initiated as early as feasible after recognition of DKA and provided in addition to standard DKA care at the treating clinician's discretion. Study assessments occur on the same schedule as the active arm (0, 10, 30, and 90 minutes) with continuous safety monitoring during and after infusion and follow-up through 90 days.

Also known as: Normal saline

Placebo (0.9% Saline) IV + Standard DKA Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>17 years.
• Unscheduled presentation to a participating emergency department with hyperglycemia (serum glucose \>250 mg/dL) and significant ketonemia consistent with DKA, defined as laboratory serum/plasma β-hydroxybutyrate (BHB) \>20 mg/dL (≈≥1.9 mmol/L).
• Note: point-of-care capillary BHB ≥1.5 mmol/L and/or breath acetone ≥0.01% may be used for screening while confirmatory labs are pending; if confirmatory BHB ≤20 mg/dL, the participant is a screen failure.
• Clinical phenotype consistent with ketosis-prone type 2 diabetes (no known prior diagnosis of type 1 diabetes).
• Able to provide written informed consent and comply with study procedures in the ED.

You may not qualify if:

• Current renal replacement therapy for chronic kidney disease (hemodialysis or peritoneal dialysis).
• Known history of type 1 diabetes mellitus or known GAD65 autoantibody positivity.
• Diagnosed cirrhosis/advanced chronic liver disease.
• Pregnancy (known pregnancy or positive test at screening).
• Known allergy or hypersensitivity to arginine or its components.
• Features of at least moderate acute alcohol intoxication at screening, per treating team.

Sponsors & Collaborators

• David K Carroll: lead
• Wayne State University: collaborator
• Detroit Medical Center: collaborator

Study Sites (1)

Detroit Medical Center

Detroit, Michigan, 48201, United States

RECRUITING

MeSH Terms

Conditions

Diabetes Mellitus; Diabetic Ketoacidosis; Diabetes Mellitus, Type 1; Hyperglycemia

Interventions

Arginine; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Ketosis; Acidosis; Acid-Base Imbalance; Diabetes Complications; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Central Study Contacts

David K Carroll, M.D.

CONTACT

16175830221; hj7218@wayne.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple-blind with centralized 1:1 allocation concealment. A site research pharmacist (unblinded) prepares study drug; infusion containers are covered to mask volume/appearance and both arms are run over 30 minutes using identical pump settings. Participants, bedside clinicians, investigators, and outcomes assessors remain blinded through database lock. Emergency unblinding is permitted for medical necessity via pharmacy access to allocation codes; all unblindings are logged. Laboratory personnel analyze specimens using coded IDs.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Emergency Medicine

Model Details: Parallel two-arm assignment in the emergency department. Each participant receives a single, 30-minute IV infusion as early as feasible after DKA is recognized, in addition to standard DKA care directed by the treating team. Arms: (1) arginine hydrochloride 30 g in 300 mL (R-Gene® 10) and (2) matching placebo (0.9% saline). No clinical care elements are withheld or mandated. Primary biomarker time points occur 10, 30 (end of infusion), and 90 minutes from infusion start; secondary outcomes include β-hydroxybutyrate clearance and total insulin dose in the first 24 h. Adults with suspected/confirmed ketosis-prone type 2 DKA are enrolled across four Detroit-area hospitals.

Study Record Dates

• First Submitted: September 4, 2025
• First Posted: September 11, 2025
• Study Start: December 19, 2025
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: February 12, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Beginning after publication of the primary results manuscript (or within 24 months of last-patient last-visit, whichever occurs first) and available for at least 5 years thereafter.
• Access Criteria: Access is provided upon reasonable request to the Study Contact listed on this record. Requestors must submit a brief proposal with analysis aims and statistical plan and provide evidence of IRB/ethics review or exemption. A Data Use Agreement is required (no re-identification, no onward sharing, secure storage, and acknowledgment of the source in resulting works). Approved requests will receive the de-identified dataset and data dictionary via secure transfer. Aggregated results will also be made available on reasonable request.

Locations

US (1)